E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
Inflammatory conditions of the large and small intestine |
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E.1.1.2 | Therapeutic area | Diseases [C] - Immune System Diseases [C20] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10011401 |
E.1.2 | Term | Crohn's disease |
E.1.2 | System Organ Class | 10017947 - Gastrointestinal disorders |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To evaluate endoscopic remission at Week 26 as assessed by ileocolonoscopy. |
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E.2.2 | Secondary objectives of the trial |
Part A
• To examine the relationship among endoscopic, imaging, histological, and clinical assessments of CD.
• To evaluate endoscopic remission at Week 14.
• To evaluate endoscopic response at Weeks 14 and 26.
• To evaluate clinical response assessed by Crohn’s Disease Activity Index (CDAI) at Weeks 10 and 26.
• To evaluate clinical remission assessed by CDAI at Weeks 10 and 26.
Part B
• To examine the relationship among endoscopic, imaging, histological, and clinical assessments of CD.
• To evaluate endoscopic remission at Week 52.
• To evaluate endoscopic response at Week 52.
• To evaluate clinical response assessed by Crohn’s Disease Activity Index (CDAI) at Week 52.
• To evaluate clinical remission assessed by CDAI at Weeks 52
• To evaluate durable endoscopic remission at Week 52 in subjects with endoscopic remission at Week 26.
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
An MREn substudy will be conducted at selected qualified centers using a standardized MR acquisition and procedure to assess bowel wall activity. Only subjects from the pre-selected sites will be included in this study; these subjects will undergo an MREn assessment at the Screening and Week 26 or ET visit, unless they have contraindications to the procedure. All MREn results will be evaluated by independent central review.
The MREn will be conducted at selected sites qualified to perform MREn as assessed by the imaging core lab designated by the sponsor. A standardized MREn acquisition protocol will be implemented across sites and detailed in an Imaging Manual. eGFR to be assessed prior to MREn being performed. MREn will be performed prior to ileocolonoscopy. De-identified MREn images will be transmitted to the imaging core lab where they will be independently analyzed by expert reviewers. Variables evaluated may include, but are not limited to, wall thickness, enhancement of bowel wall after contrast, mural edema, ulcerations, and perienteric vascularity. Bowel assessments will be made in a segmental manner to allow for direct comparison with ileocolonoscopy assessments (terminal ileum plus ascending, transverse, descending and sigmoid colon, and rectum). More proximal small bowel may also be assessed for abnormalities on MREn
only. One or more of these (including MaRIA) will be used to assess therapeutic response and will be compared to endoscopic response (SES-CD) and clinical response (CDAI) scores. |
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E.3 | Principal inclusion criteria |
- The subject has a diagnosis of moderately to severely active CD at least 3 months prior to enrollment, with a CDAI score of 220-450 during the Screening Period, a SES-CD score of ≥7 and presence of at least one mucosal ulceration documented by recorded ileocolonoscopy at Screening assessed by the central reader.
- The subject has CD with involvement of the ileum and/or colon that can be assessed by ileocolonoscopy.
- The subject has demonstrated an inadequate response to, loss of response to, or intolerance of at least 1 of the following agents as defined below:
Immunomodulators:
i. The subject has signs and symptoms of persistently active disease despite a history of at least one 12-week regimen of oral azathioprine (≥1.5 mg/kg) or
6-mercaptopurine (≥0.75 mg/kg), OR
ii. The subject has a history of intolerance (including but not limited to nausea/ vomiting, abdominal pain, pancreatitis, liver function test abnormalities, lymphopenia, thiopurine S-methyltransferase non wild type [where wild type is
defined as TPMT*1/*1], infection) to at least 1 immunomodulator.
TNF- antagonists:
i. The subject has signs and symptoms of persistently active disease despite a history of at least 1 induction with:
a) Infliximab: 4-week regimen of 5 mg/kg, 2 doses at 2 weeks apart, OR
b) Adalimumab: 2-week regimen of 160 mg on Day 1 and 80 mg on Day 15, OR
c) Certolizumab: 4-week regimen of 400 mg initially at Weeks 0, 2, 4 OR
ii. The subject has recurrence of symptoms during maintenance dosing following
prior clinical benefit (discontinuation despite clinical benefit does not qualify), OR
iii. The subject has a history of intolerance of infliximab, adalimumab, or
certolizumab, including but not limited to, infusion-related reaction,
demyelination, congestive heart failure, or infection.
Corticosteroids
i. Signs and symptoms of persistently active disease despite a history of at least one
4-week induction regimen that included a dose equivalent to prednisone 30 mg
daily orally for 2 weeks or IV for 1 week, OR
ii. Signs and symptoms of persistently active disease despite treatment with
budesonide 9 mg daily or 6 mg daily for maintenance, OR
iii. At least one failed attempt to taper corticosteroids to below a dose equivalent to prednisone 10 mg daily orally, OR
iv. History of intolerance to corticosteroids (including, but not limited to, Cushing’s
syndrome, osteopenia/osteoporosis, hyperglycemia, insomnia, and infection). |
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E.4 | Principal exclusion criteria |
- The subject has active or latent tuberculosis, regardless of treatment history, as evidenced by any of the following:
a) History of TB.
b) A diagnostic TB test performed during screening that is positive, as defined by:
i. A positive QuantiFERON® test or 2 successive indeterminate QuantiFERON tests OR
ii. A tuberculin skin test reaction ≥10 mm (≥5 mm in patients receiving the equivalent of >15 mg/day prednisone)
- The subject has chronic hepatitis B (HBV) or hepatitis C (HCV) infection.
- The subject has any identified congenital or acquired immunodeficiency (eg, common variable immunodeficiency, human immunodeficiency virus [HIV] infection, organ transplantation).
- The subject has evidence of active C. difficile infection or is having treatment for C. difficile infection or other intestinal pathogens during Screening.
- The subject has evidence of an active infection during Screening.
- The subject has received any investigational compound within 60 days of enrollment.
- The subject has received any biologics within 60 days of enrollment.
- The subject has received any live vaccinations within 30 days prior to enrollment.
- The subject has a positive PML subjective symptom checklist during screening and prior to the administration of study drug on Day 1. |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary endpoint is the proportion of subjects achieving endoscopic remission, defined as a simple endoscopic score for Crohn’s Disease (SES-CD) score of ≤ 4 at Week 26. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
-The secondary endpoints for this studyPart A are:
• Proportion of subjects achieving complete mucosal healing (defined as absence of ulceration) at Week 26.
• Proportion of subjects achieving endoscopic remission at Week 14.
• Proportion of subjects with endoscopic response (defined as SES-CD reduction by ≥50%) at Week 14.
• Proportion of subjects with endoscopic response (defined as SES-CD reduction by ≥50%) at Week 26.
• Proportion of subjects achieving clinical response (CDAI decrease from Baseline of ≥100 points) at Week 10.
• Proportion of subjects achieving clinical response (CDAI decrease from Baseline of ≥100 points) at Week 26.
• Proportion of subjects achieving clinical remission (CDAI ≤150) at Week 10.
• Proportion of subjects achieving clinical remission (CDAI ≤150) at Week 26.
The secondary endpoints for Part B are:
• Proportion of subjects achieving complete mucosal healing (defined as absence of ulceration) at Week 52.
• Proportion of subjects achieving endoscopic remission at Week 52.
• Proportion of subjects with endoscopic response (defined as SES-CD reduction by ≥50%) at Week 52.
• Proportion of subjects achieving clinical response (CDAI decrease from Baseline of ≥100 points) at Week 52.
• Proportion of subjects achieving clinical remission (CDAI ≤150) at Week 52.
• Proportion of subjects with durable clinical remission, defined as clinical remission at Week 26 and Week 52.
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 1 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 4 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 43 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
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E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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EoT will be the date of last visit of last subject at Postdose 18 week
Safety Follow-up visit.
Subjects who consent to Part B will have option to voluntarily enroll into an XAP study after Final Visit or Week 52 in MLN0002-3028. Subjects who transition into XAP study will not take part in 18-week follow-up period or the 6-month safety follow-up call following their last dose in MLN0002-3028. EoT will be the Week 52 visit for these subjects and duration of study will be approximately 56 weeks. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 2 |